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Gene Review

Arnt  -  aryl hydrocarbon receptor nuclear...

Mus musculus

Synonyms: ARNT protein, Aryl hydrocarbon receptor nuclear translocator, D3Ertd557e, Dioxin receptor, nuclear translocator, Drnt, ...
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Disease relevance of Arnt

  • These complexes regulate gene expression in response to hypoxia and xenobiotics, respectively, and mutation of the murine Arnt locus results in embryonic death by day 10.5 associated with placental, vascular, and hematopoietic defects [1].
  • Inactivation of Arnt completely suppressed the development of hemangiomas, polycythemia, and Hif-induced gene expression [2].
  • We cloned from mouse hepatoma cells a cDNA which encodes the Ah receptor nuclear translocator (Arnt) [3].
  • The unique placental phenotype of Arnt(-/-) animals also provides an important tool for studying the disease of preeclampsia [4].
  • The inhibitory domain displays specificity, in that it blocks the transactivating functions of AhR and Arnt, but not that of the herpes simplex protein VP16 [5].

High impact information on Arnt

  • Together, these data suggest an important role for decreased ARNT and altered gene expression in the impaired islet function of human type 2 diabetes [6].
  • Likewise, beta cell-specific ARNT knockout mice exhibited abnormal glucose tolerance, impaired insulin secretion, and changes in islet gene expression that mimicked those in human diabetic islets [6].
  • Loss of ARNT/HIF1beta mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes [6].
  • A heterodimer of the dioxin receptor (AhR) and Arnt, which are basic helix-loop-helix/PAS-family transcription factors, mediates most of the toxic effects of dioxins [7].
  • By generating a targeted disruption of the Arnt locus in the mouse, we show here that Arnt-/- embryonic stem cells fail to activate genes that normally respond to low oxygen tension [8].

Chemical compound and disease context of Arnt


Biological context of Arnt


Anatomical context of Arnt

  • In addition, whole-mount in situ hybridization of 9.5-day mouse embryos showed that Arnt2 mRNA was expressed in the dorsal neural tube and branchial arch 1, while Arnt transcripts were detected broadly in various tissues of mesodermal and endodermal origins [14].
  • Disruption of the Arnt gene in endothelial cells causes hepatic vascular defects and partial embryonic lethality in mice [16].
  • Expression of MyoD in HeLa cells stimulated the Arnt promoter activity by binding to the E-box [17].
  • Exon 6, encoding the conserved basic-helix-loop-helix domain of the protein, was flanked by loxP sites and introduced into the Arnt gene by standard gene disruption techniques using embryonic stem cells [18].
  • Arnt concentration was not affected by TCDD in these cell lines [19].

Associations of Arnt with chemical compounds


Physical interactions of Arnt

  • MA10 cells also exhibit cAMP-dependent AhR down-regulation and AhR/Arnt complex formation [22].
  • Treatment with the proteasome inhibitor MG132 increased endogenous Sp1 phosphorylation and its DNA-binding activity to the ARNT promoter [23].
  • Formation of neural ARNT2/HIF-1alpha complexes in Arnt(-/-) ES cell-derived teratocarcinomas may explain why these tumors express VEGF, vascularize and grow efficiently, in contrast to ARNT-deficient hepatomas [24].
  • The ligand-activated aromatic hydrocarbon receptor (AHR) dimerizes with the AHR nuclear translocator (ARNT) to form a functional complex that transactivates expression of the cytochrome P-450 CYP1A1 gene and other genes in the dioxin-inducible [Ah] gene battery [25].

Enzymatic interactions of Arnt

  • In order to minimize any artificial steric hindrances to dimerization and XRE binding, each Ahr mutant was also tested with an equivalently deleted Arnt mutant [15].

Regulatory relationships of Arnt

  • Genetic analyses reveal that induction is abolished in aromatic hydrocarbon receptor (AhR)- or aromatic hydrocarbon receptor nuclear translocator (Arnt)-defective variants but restored upon reconstitution of the variant cells with cDNAs expressing functional AhR or Arnt [26].
  • Co-transfection of CHF1 inhibited ARNT/EPAS1-dependent transcription by 85%, and this inhibition is dose-dependent [27].

Other interactions of Arnt

  • 5. These findings define the temporal regulation of receptor activation during normal ontogeny and provide evidence to support the idea that receptor activation and AHR-ARNT heterodimerization are essential for normal vascular development [20].
  • Targeted mutation of the murine arylhydrocarbon receptor nuclear translocator 2 (Arnt2) gene reveals partial redundancy with Arnt [1].
  • This places Ctsk approximately 4.5 kb downstream of Arnt on mouse chromosome 3 at locus 47.9 [28].
  • Interaction of the regulatory domains of the murine Cyp1a1 gene with two DNA-binding proteins in addition to the Ah receptor and the Ah receptor nuclear translocator (ARNT) [29].
  • BPA dose-independently up-regulated the expression of AhRR and Arnt in mid- and late-stage embryos [30].

Analytical, diagnostic and therapeutic context of Arnt


  1. Targeted mutation of the murine arylhydrocarbon receptor nuclear translocator 2 (Arnt2) gene reveals partial redundancy with Arnt. Keith, B., Adelman, D.M., Simon, M.C. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  2. Inactivation of the arylhydrocarbon receptor nuclear translocator (Arnt) suppresses von Hippel-Lindau disease-associated vascular tumors in mice. Rankin, E.B., Higgins, D.F., Walisser, J.A., Johnson, R.S., Bradfield, C.A., Haase, V.H. Mol. Cell. Biol. (2005) [Pubmed]
  3. Transcriptional activation function of the mouse Ah receptor nuclear translocator. Li, H., Dong, L., Whitlock, J.P. J. Biol. Chem. (1994) [Pubmed]
  4. Placental cell fates are regulated in vivo by HIF-mediated hypoxia responses. Adelman, D.M., Gertsenstein, M., Nagy, A., Simon, M.C., Maltepe, E. Genes Dev. (2000) [Pubmed]
  5. Transcriptional activation by the mouse Ah receptor. Interplay between multiple stimulatory and inhibitory functions. Ma, Q., Dong, L., Whitlock, J.P. J. Biol. Chem. (1995) [Pubmed]
  6. Loss of ARNT/HIF1beta mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes. Gunton, J.E., Kulkarni, R.N., Yim, S., Okada, T., Hawthorne, W.J., Tseng, Y.H., Roberson, R.S., Ricordi, C., O'Connell, P.J., Gonzalez, F.J., Kahn, C.R. Cell (2005) [Pubmed]
  7. Modulation of oestrogen receptor signalling by association with the activated dioxin receptor. Ohtake, F., Takeyama, K., Matsumoto, T., Kitagawa, H., Yamamoto, Y., Nohara, K., Tohyama, C., Krust, A., Mimura, J., Chambon, P., Yanagisawa, J., Fujii-Kuriyama, Y., Kato, S. Nature (2003) [Pubmed]
  8. Abnormal angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein ARNT. Maltepe, E., Schmidt, J.V., Baunoch, D., Bradfield, C.A., Simon, M.C. Nature (1997) [Pubmed]
  9. Mechanisms of ligand-induced aryl hydrocarbon receptor-mediated biochemical and toxic responses. Wilson, C.L., Safe, S. Toxicologic pathology. (1998) [Pubmed]
  10. Recruitment of thyroid hormone receptor/retinoblastoma-interacting protein 230 by the aryl hydrocarbon receptor nuclear translocator is required for the transcriptional response to both dioxin and hypoxia. Beischlag, T.V., Taylor, R.T., Rose, D.W., Yoon, D., Chen, Y., Lee, W.H., Rosenfeld, M.G., Hankinson, O. J. Biol. Chem. (2004) [Pubmed]
  11. Patent ductus venosus and dioxin resistance in mice harboring a hypomorphic Arnt allele. Walisser, J.A., Bunger, M.K., Glover, E., Harstad, E.B., Bradfield, C.A. J. Biol. Chem. (2004) [Pubmed]
  12. Aryl hydrocarbon receptor regulation of ceramide-induced apoptosis in murine hepatoma 1c1c7 cells. A function independent of aryl hydrocarbon receptor nuclear translocator. Reiners, J.J., Clift, R.E. J. Biol. Chem. (1999) [Pubmed]
  13. Identification of the Ah receptor nuclear translocator protein (Arnt) as a component of the DNA binding form of the Ah receptor. Reyes, H., Reisz-Porszasz, S., Hankinson, O. Science (1992) [Pubmed]
  14. cDNA cloning and tissue-specific expression of a novel basic helix-loop-helix/PAS factor (Arnt2) with close sequence similarity to the aryl hydrocarbon receptor nuclear translocator (Arnt). Hirose, K., Morita, M., Ema, M., Mimura, J., Hamada, H., Fujii, H., Saijo, Y., Gotoh, O., Sogawa, K., Fujii-Kuriyama, Y. Mol. Cell. Biol. (1996) [Pubmed]
  15. Identification of functional domains of the aryl hydrocarbon receptor. Fukunaga, B.N., Probst, M.R., Reisz-Porszasz, S., Hankinson, O. J. Biol. Chem. (1995) [Pubmed]
  16. Disruption of the Arnt gene in endothelial cells causes hepatic vascular defects and partial embryonic lethality in mice. Yim, S.H., Shah, Y., Tomita, S., Morris, H.D., Gavrilova, O., Lambert, G., Ward, J.M., Gonzalez, F.J. Hepatology (2006) [Pubmed]
  17. Structure and expression of the mouse AhR nuclear translocator (mArnt) gene. Wang, F., Gao, J.X., Mimura, J., Kobayashi, A., Sogawa, K., Fujii-Kuriyama, Y. J. Biol. Chem. (1998) [Pubmed]
  18. Conditional disruption of the aryl hydrocarbon receptor nuclear translocator (Arnt) gene leads to loss of target gene induction by the aryl hydrocarbon receptor and hypoxia-inducible factor 1alpha. Tomita, S., Sinal, C.J., Yim, S.H., Gonzalez, F.J. Mol. Endocrinol. (2000) [Pubmed]
  19. The aryl-hydrocarbon receptor, but not the aryl-hydrocarbon receptor nuclear translocator protein, is rapidly depleted in hepatic and nonhepatic culture cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Pollenz, R.S. Mol. Pharmacol. (1996) [Pubmed]
  20. Gestational exposure of Ahr and Arnt hypomorphs to dioxin rescues vascular development. Walisser, J.A., Bunger, M.K., Glover, E., Bradfield, C.A. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  21. The aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator protein show distinct subcellular localizations in Hepa 1c1c7 cells by immunofluorescence microscopy. Pollenz, R.S., Sattler, C.A., Poland, A. Mol. Pharmacol. (1994) [Pubmed]
  22. Cell selective cAMP induction of rat CYP1B1 in adrenal and testis cells. Identification of a novel cAMP-responsive far upstream enhancer and a second Ah receptor-dependent mechanism. Zheng, W., Brake, P.B., Bhattacharyya, K.K., Zhang, L., Zhao, D., Jefcoate, C.R. Arch. Biochem. Biophys. (2003) [Pubmed]
  23. Proteasome inhibition induces nuclear translocation of the dioxin receptor through an Sp1 and protein kinase C-dependent pathway. Santiago-Josefat, B., Fernandez-Salguero, P.M. J. Mol. Biol. (2003) [Pubmed]
  24. The role of ARNT2 in tumor angiogenesis and the neural response to hypoxia. Maltepe, E., Keith, B., Arsham, A.M., Brorson, J.R., Simon, M.C. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  25. Constitutive activation of the aromatic hydrocarbon receptor. Chang, C.Y., Puga, A. Mol. Cell. Biol. (1998) [Pubmed]
  26. Induction and superinduction of 2,3,7,8-tetrachlorodibenzo-rho-dioxin-inducible poly(ADP-ribose) polymerase: role of the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator transcription activation domains and a labile transcription repressor. Ma, Q. Arch. Biochem. Biophys. (2002) [Pubmed]
  27. Cardiovascular basic helix loop helix factor 1, a novel transcriptional repressor expressed preferentially in the developing and adult cardiovascular system. Chin, M.T., Maemura, K., Fukumoto, S., Jain, M.K., Layne, M.D., Watanabe, M., Hsieh, C.M., Lee, M.E. J. Biol. Chem. (2000) [Pubmed]
  28. Complete genomic structure of the mouse cathepsin K gene (Ctsk) and its localization next to the Arnt gene on mouse chromosome 3. Rantakokko, J., Kiviranta, R., Eerola, R., Aro, H.T., Vuorio, E. Matrix Biol. (1999) [Pubmed]
  29. Interaction of the regulatory domains of the murine Cyp1a1 gene with two DNA-binding proteins in addition to the Ah receptor and the Ah receptor nuclear translocator (ARNT). Carrier, F., Chang, C.Y., Duh, J.L., Nebert, D.W., Puga, A. Biochem. Pharmacol. (1994) [Pubmed]
  30. Effects of exposure in utero to bisphenol a on the expression of aryl hydrocarbon receptor, related factors, and xenobiotic metabolizing enzymes in murine embryos. Nishizawa, H., Imanishi, S., Manabe, N. J. Reprod. Dev. (2005) [Pubmed]
  31. Structure and expression of the Ah receptor repressor gene. Baba, T., Mimura, J., Gradin, K., Kuroiwa, A., Watanabe, T., Matsuda, Y., Inazawa, J., Sogawa, K., Fujii-Kuriyama, Y. J. Biol. Chem. (2001) [Pubmed]
  32. Identifying target genes of the aryl hydrocarbon receptor nuclear translocator (Arnt) using DNA microarray analysis. Wang, F., Shi, S., Zhang, R., Hankinson, O. Biol. Chem. (2006) [Pubmed]
  33. A point mutation responsible for defective function of the aryl-hydrocarbon-receptor nuclear translocator in mutant Hepa-1c1c7 cells. Numayama-Tsuruta, K., Kobayashi, A., Sogawa, K., Fujii-Kuriyama, Y. Eur. J. Biochem. (1997) [Pubmed]
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